Compounds containing a thione group are widely used in industry and agriculure. Collectively, these compounds produce injury to several organs, including lung, liver and kidney. A growing body of evidence suggests that intermediates in their metabolism via pathways of "oxidative desulfurization" may be the actual toxic species. In two cases, S-oxides of the thione compound have been identified and evidence presented for their role in toxicity. In no case have the enzymatic pathways or intermediates involved in the metabolism of these compounds been elucidated. We have recently shown that a series of para-substituted thiobenzamides fulfill the requirements of being a useful series of model toxins for studying the toxic biotransformation of thione compounds. Two significant aspects of their toxicity are: 1) their capacity to produce hepatotoxicity varies in accordance with the electron donating properties of substituents in the para position of the ring and 2) N-substituents shift the site of injury to the lung and produce pulmonary edema and hydrothorax. We propose to study the metabolism and toxicity of a series of para and N-substituted thiobenzamide derivatives with the following objectives: 1) elucidation of the enzymes and intermediates involved; 2) determination of the physiochemical properties of the intermediates, particularly S-oxides; 3) evaluation of the toxic effect of the S-oxide vis-a-vis the parent thiobenzamide. N- and ring-substituted thiobenzamides and their S-oxides will be synthesized. Analytical methodology for monitoring the thiobenzamides and their metabolites in tissues will be developed. The toxicity and chemical reactivity of N- and ring-substituted thiobenzamides and their S-oxides will be characterized. The in vitro microsomal protein binding and metabolism of radio-labeled thiobenzamides and their S-oxides will be studied using doubly-labeled compounds. Information obtained from the binding studies will be used to make inferences about the nature of thiobenzamide's biotransformation to reactive metabolites. The in vivo metabolic profile of the thiobenzamides and their S-oxide will be determined in blood and their target organs. In vivo covalent binding and excretion studies will be carried out.